GB2262281A - Synthesis of 3-exomethylene-cephams - Google Patents

Description

2262281 PROCESS FOR THE SYNTHESIS OF CEPHAMS The present invention relates

to the preparation of cephams which are useful intermediates for the production of many useful fl-lactam antibiotics.

It is known that penicillin sulfoxide yields cephems, and exomethylenecephams in a very small amount, upon heating in the presence of acid catalysts (Chemistry and biology of 8-lactam antibiotics, Vol.I, Morin-Gormann ed., 1982, pp 93-95). A lot of work has been done in order to increase the proportion of exomethylenecephams by changing the protective group in the 4 position (Chemistry and Biology of P-Lactam Antibiotics, Vol.1, Morin and Gorman Ed., Academic Press, p.96, 1982). There are other methods for the synthesis of these valuable products, but they all require at least a two step synthesis.

There is still the need for a short synthesis that in one-step could transform penam sulphoxides into valuable exomethylenecephams. We now wish to disclose a new ring enlargement which principally affords exomethylenecephams, involving the conversion of penam sulfoxides into exomethylenecephams in one single step.

The process has many advantages including the advantage that, starting from the cheap penam nucleus, it leads in one step to the production of valuable compounds which are key intermediates for the production of many useful P-lactam antibiotics (Chemistry and Biology of P-Lactam Antibiotics, Vol.1, Morin and Gorman Ed., Academic Press, p.94, 1982). Accordingly, the present invention provides a process which comprises reacting a compound of formula (II) 0I z R37 N 0 - COOR2 (II) wherein each of R, and R2 isr independently hydrogen or an organic residue with a radical initiator in the presence of molelcular oxygen, typically pure 02 or air, to give a compound of formula (I); RI- r.

N 0 ic 0 COOR2 (I) wherein R, and R2 are as above defined.

The reaction is typically carried out in a suitable solvent with up to 10 equivalents, preferably from 0. 1 to 3 equivalents, of the radical initiator. The temperature at which the reaction is performed is suitably from OOC to 2000C, typically at the solvent refluxing temperature. The reaction time ranges from 1 hour to a few days, preferably for a few hours, e.g. from 2 to 10 hours, such as from 2 to 6 hours.

Suitable solvents are organic solvents which are known to be inert to the reaction conditions, such as aromatic or aliphatic solvents. Preferred solvents include benzene, toluene, and xylenes.

The radical initiator may suitably be selected from azobisisobutyrronitrile (AIBN), benzoyl peroxide, t-butyl hydroperoxide, di-t-butylperoxide. Preferred compounds are AIBN and benzoyl peroxide.

The organic residues which R, may represent include a linear or branched Cl-C4 alkanoyl group; an optionally substituted benzoyl; a linear or branched C8-C12 phenylalkanoyl group; a linear or branched CS-C12 phenoxyalkanoyl group; aphthalimido group; a linear or branched C6-CIO thienylalkanoyl group and a linear or branched C4-C8 (1,3,4thiodiazolyl)thicalkancyl residue; the organic residues which R2 nay represent include a carboxy protecting group chosen from linear or branched Cl-C4 alkyl, trihalcalkyl group, an optionally substituted benzyl, a Cl-C4 trialkylsilyl, an optionally substituted diphenyl methyl, or a C2-C5 alkenyl group.

When R, is an optionally substituted benzoyl, the phenyl ring is optionally substituted by one or more substituents chosen from: i) Cl-C4 linear or branched alkyl group, ii) N02r iii) Cl-C4 linear or branched alkoxyl group, or iv) a halogen atom. When R2 is an optionally substituted benzyl, the phenyl ring is optionally substituted by one or more substituents chosen from: i) Cl-C4 linear or branched alkyl group, ii) N02r iii) Cl-C4 linear or branched alkoxyl group, or iv) an halogen atom.

When R2 is an optionally substituted diphenyl methyl group, each of the phenyl rings may be independently substituted by by one or more substituents chosen from: i) Cl-Ct linear or - 4 branched alkyl group, ii) N02r iii) Cl-C4 linear or branched alkoxyl group, or iv) an halogen atom.

Preferred groups which R, ziay represent include optionally substituted benzoyl, preferably a benzoyl group; a linear or branched Ce-CI2 phenylalkanoyl group, and preferably a phenylacetyl group; a linear or branched CO-CI2 phenoxyalkanoyl group, and preferably a phenoxyacetyl group; a linear or branched C6-CIO thienylalkanoyl group. and preferably a thienylacetyl group; a Cl-C4 alkanoyl group. Preferred R2 are chosen from linear or branched Cl-C4 alkyl, preferably methyl, ethyl, or t-butyl; a benzhidryl group; a trihaloalkyl group, preferably 2,2,2 trichloroethyl. Among the benzyl groups, benzyl, p-nitrobenzyl, and p- methoxybenzyl groups are preferred. A trialkylsilyl group means preferably a trimethylsilyl, or a t-butyldinethylsilyl group. Among the optionally substituted benzhidryl groups, the benzhidryl group is preferred.

The starting materials of formula II are known or may be prepared by known methodologies.

The separation of the obtained cephams of formula I may be performed, if desired, by known methodologies (e.g. by oxidation to sulphoxides).

A compound of formula (I) may, in a subsequent step, be converted into a fl-lactam antibiotic.

The P-lactam antibiotic thus produced may be formulated with a pharmaceutically acceptable carrier or diluent to yield a pharmaceutical composition. The composition may be suitable for oral, topical or parenteral. administration to a human or nimal subject.

The following examples further illustrate the present invention.

Example 1

To a solution of 5g of methyl 7-phenoxyacetamido-penam-3-carboxylate-loxide in 600 ml of toluene, 1.60g of AIBN were added. The reaction was heated to reflux in the presence of 02 for six hours. During this time further 1.6g of AIBN were added in portions. The reaction mixture was evaporated in vacuo, and the products were isolated by column chromatography eluting with ethyl acetate/hexanes mixtures. There were obtained 0.979 of methyl 7p-phenoxyacetamido-3-methylenecepham4carboxylate.

NMR (CDC13) 8 ppn,: 3.18 and 3.68 (2H, two d, J= 14 Hz), 3.75 (3H, s), 4. 52 (2H, s), 5.11 (1H, s), 5.23 (IH, br s), 5.25 (1H, s), 5. 4 3 (1H, d, J=4. 5 Hz), 5. 7 3 (1H, dd, J=4. 5 and 9. 5 Hz), 6.85-7.40 (6H, m).

Mass (FD, m/e): 362 (M).

By analogy according to the above described example the following compounds were prepared:

Benzyl 7B-Dhenoxyacetamido-3-Tnethylenecezham-4carboxylate. Benzyl 7anhenylacetamido-3-methyleneceDhan,-4carboL<Mlate.

Example 2

The reaction was performed as in the example above, except that - 6 xylene was used as solvent. After 1 hour the reaction was worked up as in example 1, giving analogous results.

By analogy according to the above described examplethe following compounds were prepared:

1D-Methoxvbenzyl 70-Dhenoxvacetamido-3-methvleneceDham-4- carboxvIate.

R-MethoUbenzyl carboxvlate.

7B-iDhenylacetamido-3-methvlenecei:)ham-4- Example 3

The reaction was carried out as in example 1, but a stream of air was used instead of oxygen. The product of example 1 was isolated in analoguos yield.

By analogy according to the above described example the following compounds were prepared: t-Butyl 7R-phenoxvacetamido-3-methvleneceiDham4carboxvlate. t-Butyl 7C-phenylacetamido-3-nethvlenecenham-4carboxvlate.

Example 4

0 To a solution of 0.5g of the starting product in example 1 in 60 ml of refluxing toluene, a solution of 0.32g of AIBN in 20 ml of toluene was dropped over a period of 24 hours. After the usual work-up the desired product was isolated in 30% yield.

By analogy according to the above described examples the following compounds were prepared:

2.2.2-Trichloroethvl 70-Dhenoxvacetamido-3-methvleneceDham-4 carboxylate.

2.2,2-Trichloroethvl 7B-Dhenvlacetamido-3-inethvleneceinham-4carboxylate.

Claims (13)

1. A process for preparing a compound of formula R,. r.

N 0 ic CWP2 (I) wherein each of R, and R2 is. independently, hydrogen or an organic residue, which process comprises reacting a compound of formula 11 0- 1+ R,:- 5 N 0 -11.

R (II) 2 wherein R, and R2 are as above defined, with a radical initiator in the presence of molecular oxygen.

2. A process according to claim 1 in which R, is hydrogen or a linear or branched Cl-C4 alkanoyl group, an optionally substituted benzoyl, a linear or branched C8-C 12 phenylalkanoyl group, a linear or branched C8- C12 phenoxy alkanoyl group, a phthalimido group, or a linear or branched C4-C8 (1,3,4-thiadiazolyl)thioalkyanoyl residue; and R2 is hydrogen or a carboxy protecting group selected from a linear or branched Cl-C4 alkyl, a trihaloalkyl, an optionally substituted benzyl, a Cl-C4 trialkylsilyl, an optionally substituted diphenyl methyl, and a Cl-C5 alkenyl group.

3. A process according to claim 1 or 2 wherein the reaction is carried out with up to 10 equivalents of the radical initiator.

4. A process according to any one of the preceding claims wherein the reaction is performed at a temperature of from OOC to 2000C.

5. A process according to any one of thepreceding claims wherein the reaction is carried out in an organic solvent inert to the reaction conditions.

6. A process according to any preceding claims wherein the reaction solvent refluxing temperature for 2 to 10 hours.

7. A process according to claim 5 or 6 in Vhich the solvent is selected from benzene, toluene and xylene.

S. A process according to any one of the preceding claims wherein the reaction is carried out with 0.1 to 3 equivalents of the radical initiator.

9. A process according to any one of the preceding claims wherein the radical initiator is selected from azobisisobutirronitrile (AIBN), benzoyl peroxide, tbutyl hydroperoxide and di-t-butylperoxide.

10. A process according to any one of the preceding claims which further comprises converting the compound of formula (I) into a P-lactam antibiotic.

11. A process according to claim 10 which further comprises formulating the P-lactam antibiotic with a pharmaceutically acceptable carrier or diluent.

12. A process according to any one of the preceding claims which is carried out in the presence of pure oxygen.

13. A process according to any one of claims 1 to 11 which is carried out in the presence of air.

one of the is nerformed at the